The histamine H3 receptor is primarily expressed in the mammalian central nervous system (CNS), with some minimal expression in peripheral tissues such as vascular smooth muscle. Several indications for histamine H3 antagonists and inverse agonists have been proposed based on animal pharmacology and other experiments with known histamine H3 antagonists (e.g. thioperamide). (See: “The Histamine H3 Receptor-A Target for New Drugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000, 408, 860-864.) These include conditions such as cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.
Compounds that possess histamine H3 receptor activity and serotonin transporter (SERT) activity may be useful in the treatment of SERT-mediated disorders such as substance abuse disorders and sexual dysfunction (including premature ejaculation), and particularly beneficial in the treatment of depression. Activation of the H3 receptor on neurons by histamine or an agonist decreases the release of several neurotransmitters including noradrenaline and serotonin, key neurotransmitters involved in depression (Hill, S. J. et al. Pharmacol. Rev. 1997, 49(3), 253-278). Although H3 receptor antagonists alone may not be capable of increasing serotonin levels in vivo to those required for antidepressant effects, concomitant blockade of the SERT will simultaneously decrease the neuronal reuptake of these neurotransmitter molecules, leading to enhanced concentrations of serotonin in the synaptic cleft and an enhanced therapeutic effect and a potentially reduced side effect profile as compared to a compound with SERT activity alone.
Histamine H3 antagonists have been shown to have pharmacological activity relevant to several key symptoms of depression, including sleep disorders (e.g. sleep disturbances, fatigue, and lethargy) and cognitive difficulties (e.g. memory and concentration impairment), as described above. Therefore, a combined H3/SERT modulating compound would provide symptomatic relief for the sleep disorders, fatigue, and cognitive problems during the first weeks of treatment, before the mood-elevating effect of the SERT modulation is noticed.
Carbon-linked substituted benzyl amine compounds have been described by Pfizer as selective serotonin reuptake inhibitors, in Intl. Patent Publ. Nos. WO 01/72687 and WO 02/18333, and in U.S. Patent Appl. Publ. No. 2002/0143003. Heteratom-linked aryl benzamides have been described by Glaxo SmithKline, in Intl. Patent Appl. Publ. No. WO 05/040144. Diphenyl ether compounds are described as monoamine reuptake inhibitors by Pfizer in Intl. Patent Publ. No. WO 2007/036781.
Compounds that have H3 receptor activity and SERT activity have been disclosed in U.S. Pat. Publ. US 2006/0194837 A1 (published Aug. 31, 2006; based on U.S. patent application Ser. No. 11/300,880), U.S. Pat. Publ. US 2006/0293316 A1 (published Dec. 28, 2006; based on U.S. patent application Ser. No. 11/424,734), and U.S. Pat. Publ. US 2006/0287292 A1 (published Dec. 21, 2006; based on U.S. patent application Ser. No. 11/424,751), each of which is hereby incorporated by reference.
However, there remains a need for potent histamine H3 receptor and/or serotonin transporter modulators with desirable pharmaceutical properties.